LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.

Schwarz LJ, Fox EM, Balko JM, Garrett JT, Kuba MG, Estrada MV, González-Angulo AM, Mills GB, Red-Brewer M, Mayer IA, Abramson V, Rizzo M, Kelley MC, Meszoely IM, Arteaga CL
J Clin Invest. 2014 124 (12): 5490-502

PMID: 25401474 · PMCID: PMC4348968 · DOI:10.1172/JCI72573

Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.

MeSH Terms (25)

Amino Acid Substitution Aminopyridines Animals Breast Neoplasms Dasatinib Drug Resistance, Neoplasm Drug Synergism Estrogen Receptor Modulators Female Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Mice Mice, Nude Morpholines Mutation, Missense Phosphatidylinositol 3-Kinases Phosphorylation Protein Kinase Inhibitors Pyrimidines Receptors, Estrogen src-Family Kinases src Homology Domains Thiazoles Xenograft Model Antitumor Assays

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